Molecular and genetic mechanisms of plasticity in addiction

Drugs of abuse result in well-characterized changes in synapse function and number in brain reward regions such as the nucleus accumbens. However, recent reports demonstrate that only a small fraction of neurons in the nucleus accumbens are activated in response to psychostimulants such as cocaine. While these "ensemble" neurons are marked by drug-related transcriptional changes in immediate early genes, the mechanisms that ultimately link these early changes to enduring molecular alterations in the same neurons are less clear. In this review, we 1) describe potential mechanisms underlying regulation of diverse plasticity-related gene programs across drug-activated ensembles, 2) discuss factors conferring ensemble recruitment bias within seemingly homogeneous populations, and 3) speculate on the role of chromatin and epigenetic modifiers in gating metaplastic state transitions that contribute to addiction.